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Abstract

Introduction

Co-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients
with rheumatoid arthritis (RA). Most published studies in this field are retrospective
or cross sectional. We investigated the presence of traditional and disease related
risk factors for CVD at the onset of RA and during the first five years following
diagnosis. We also evaluated their potential for predicting a new cardiovascular event
(CVE) during the five-year follow-up period and the modulatory effect of pharmacological
treatment.

Methods

All patients from the four northern-most counties of Sweden with early RA are, since
December 1995, consecutively recruited at diagnosis (T0) into a large survey on the
progress of the disease. Information regarding cardiovascular co-morbidity and related
predictors was collected from clinical records and supplemented with questionnaires.
By April 2008, 700 patients had been included of whom 442 patients had reached the
five-year follow-up (T5).

Results

Among the 442 patients who reached T5 during the follow-up period, treatment for hypertension
increased from 24.5 to 37.4% (P < 0.001)), diagnosis of diabetes mellitus (DM) from 7.1 to 9.5% (P < 0.01) whilst smoking decreased from 29.8 to 22.4% (P < 0.001) and the BMI from 26.3 to 25.8 (P < 0.05), respectively. By T5, 48 patients had suffered a new CVE of which 12 were
fatal. A total of 23 patients died during the follow-up period. Age at disease onset,
male sex, a previous CVE, DM, treatment for hypertension, triglyceride level, cumulative
disease activity (area under the curve (AUC) disease activity score (DAS28)), extra-articular
disease, corticosteroid use, shorter duration of treatment with disease modifying
anti-rheumatic drugs (DMARDs) and use of COX-2 inhibitors increased the hazard rate
for a new CVE. A raised erythrocyte sedimentation rate (ESR) at inclusion and AUC
DAS28 at six months increased the hazard rate of CVE independently whilst DMARD treatment
was protective in multiple Cox extended models adjusted for sex and CV risk factors.
The risk of a CVE due to inflammation was potentiated by traditional CV risk factors.

Conclusions

The occurrence of new CV events in very early RA was explained by traditional CV risk
factors and was potentiated by high disease activity. Treatment with DMARDs decreased
the risk. The results may have implications for cardio-protective strategies in RA.

Introduction

Mortality due to cardiovascular disease (CVD) is increased in patients with rheumatoid
arthritis (RA) [1-8]. Several studies confirm that also cardiovascular (CV) morbidity is increased in
patients with RA compared with controls [5,7-11]. According to most previous reports, traditional risk factors for CVD cannot fully
explain this fact [3,5,10,12,13]. We have previously reported morbidity and case fatality due to myocardial infarction
(MI) to be increased in patients with established RA from Northern Sweden, compared
with the general population [9]. Hypertension was the only traditional CV risk factor that clearly predicted a CVE
[9,13]. Although some controversy may exist over the statement [14], the inflammatory response is implicated as being predictive of CVD in patients with
RA [13,15,16] and appears to potentiate the effect of traditional CV risk factors [17]. Most published studies in this field are, however, retrospective or cross sectional,
and are often hospital-based and comprise information from medical records and various
registers. Such studies are occasionally subject to deficiencies; for example, patients
with low disease activity, patients moving out of the study region, and those suffering
a premature death are lost. In order to focus on the progression of CVD during the
course of a rheumatoid disease and to evaluate related risk factors in early RA, a
prospective design is necessary.

The present observational study was designed to follow patients with early RA prospectively
from disease onset. The aim was: first, to investigate the presence of traditional
and disease related CV risk factors, at the onset of RA and during the first five
years following diagnosis, in a large cohort of patients; second, to evaluate prospectively
the predictive effect of these factors for CVD, as measured by the first CVE during
follow-up; and finally, to assess the potential modulating effect(s) of the prescribed
pharmacological treatment.

Materials and methods

By reference to the nation-wide Swedish Rheumatoid Arthritis Registry [18] all eligible patients from the four northern-most counties of Sweden diagnosed with
early RA (that is, symptomatic for <12 months), and fulfilling the American Rheumatism
Association classification criteria [19] are since December 1995 consecutively included in a large survey on the progress
of RA and development of co-morbidity, in particular CVD. By April 2008, 700 patients
(481 women, 219 men) registered with newly diagnosed early RA had been included in
the study at diagnosis of RA (baseline, T0). Of these, 442 patients reached T5, that
is, they had suffered their disease for more than five years. All patients had been
assessed regularly by their local rheumatologist during the follow-up period with
special attention to established CV risk factors, any previous CVE, and clinical examination
including blood pressure and laboratory tests. The following parameters were recorded
at baseline and after 6, 12, 18, 24, 36, and 60 months: the 28-joint count of tender
and swollen joints; a visual analogous scale (VAS) for pain and patient's global assessment;
completion of a Health Assessment Questionnaire (HAQ) [20] and inflammatory markers, that is, erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP). Disease activity score (DAS28) [21] was calculated. Lipid levels (total cholesterol (mmol/L), high-density lipoprotein
(HDL, mmol/L) and triglycerides (mmol/L)) were analysed in the majority of cases at
baseline, otherwise as soon as possible during the follow-up period. The presence
of autoantibodies, that is, rheumatoid factor (RF), and anti-nuclear antibodies (ANA),
was detected at baseline by the routine methods at each hospital. Antibodies against
cyclic citrullinated peptides/proteins (ACPA) were analysed at baseline using enzyme-linked
immunoassays (ELISA) for anti-CCP antibodies type 2. Genotyping for PTPN22 1858C/T
polymorphisms was performed for the majority of the patients using the 5' -nuclease
assay [22,23] and for HLA -DRB1 using polymerase chain reaction sequence-specific primers from
a DR low-resolution kit and DRB1*04 sub-typing kit (Dynal, Oslo, Norway) as described
previously [24]. In the present work the shared epitope (SE) alleles were defined as HLA-DRB1*0401
or DRB1*0404.

All patient records were carefully read and data collected according to a study protocol,
both at inclusion at T0 and after five years at T5. In addition, the patients completed
a self-reported questionnaire on co-morbidity at T0 and at T5 to further increase
the validity of the collected data. Recorded variables were: all co-morbidity including
previous CVE, that is, prior to inclusion, and new CVE during follow-up, that is,
myocardial infarction (MI)/coronary artery bypass grafting (CABG), stroke/transient
ischaemic attack (TIA)/deep vein thrombosis (DVT)/pulmonary embolism (PE), and ruptured
aortic aneurysm. Myocardial infarction was recorded when the diagnosis had been made
according to the World Health Organization (WHO) criteria [25]. A cerebrovascular lesion was recorded when intra-cerebral haemorrhage or cerebral
infarction had been diagnosed by either computerized tomography or magnetic resonance
imaging, or when a typical clinical profile of neurological deficits had persisted
for more than 24 h. A TIA was recorded in cases when the focal neurological deficit
of presumed ischaemic origin had persisted for less than 24 h. Deep vein thrombosis/pulmonary
embolism was recorded when the diagnosis had been verified objectively (by phlebography,
sonography, scintigraphy, and/or arteriography), or when the clinical signs combined
with pulmonary radiography, electrocardiography, and laboratory changes resulted in
full time warfarin treatment. The information regarding fatal cardiovascular events
was obtained from the National Board of Health and Welfare. Furthermore, traditional
CV risk factors (ongoing treatment for hypertension and current blood pressure, diabetes
mellitus (DM), smoking (current and previous), body mass index (BMI)), rheumatoid
nodules and time for development of extra-articular disease (EAD) [26] were registered. Cumulated pharmacological treatment was registered (months before
inclusion and during follow-up) regarding corticosteroids and disease modifying anti-rheumatic
drugs (DMARDs, that is, methotrexate, sulfasalazine, chloroquine, azathioprine, mycophenolatmophetil,
myocrisine, auranofin, cyclosporine, leflunomid, alkylating cytotoxic agents) including
biological agents (etanercept, adalimumab, infliximab, anakinra, rituximab) at inclusion
and at follow-up. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs), before
inclusion (T0) and any period during the follow-up period (T5) was registered as "yes"
or "no", as was treatment with statins - regarded as a proxy for presence of hyperlipidaemia.
Time for treatment with selective cyclo-oxygenase-2 (COX-2) inhibitors was registered
as exact as possible.

The first 128 patients included from two of the counties fulfilled the criteria for
inclusion in the Swedish RA-registry but were, due to a lack of personnel resources,
not recorded regularly. These patients were followed up in the same way as the other
patients regarding base line data on inflammatory variables, autoantibodies, SE, pharmacological
treatment, CV risk factors and previous and new CV events; however, they lack regularly
recorded data on laboratory results, VAS scales and joint counts during the follow-up
period. These patients did not differ significantly from the rest of the cohort when
comparing ESR at baseline.

The regional Ethics Committee at the University Hospital of Umeå approved this study
and all participants gave their written informed consent in accordance with the Declaration
of Helsinki.

Statistical analysis

The integral of disease activity, DAS28, was calculated in order to evaluate the total
burden of disease activity over time and is referred to as the area under the curve
(AUC) of DAS28 at 6, 12 and 24 months after inclusion into the study. When RA register
data were missing, the last value was used to impute data once for each parameter
assessed. Furthermore, for the regression analyses, imputations were made as follows:
for AUC DAS28 at 6, 12 and 24 months respectively, the patient sample was divided
into two groups, that is, censored and uncensored patients. Patients were censored
after the time of the first event after inclusion or death or end of study. When values
were missing for a single patient in each group respectively, data values were assigned
by simple random sampling with replacement of values from patients with non-missing
values, thus each missing value was replaced with an observed value. The same method
was used for censored patients lacking data on levels of triglycerides.

For comparison of means of data and proportions between two sub-groups, unpaired t-test
and Chi-squared tests were used, respectively. For comparison of recurrent data in
the same individuals between variables at baseline (T0) and those collected at follow-up
(T5), paired t-tests and McNemar's test for binary data were used.

For the regression analyses, time dependent variables were created for some variables:
for extra articular disease (EAD), the variable time-EAD indicates when EAD occurred
and time t when a CVE or a censoring has occurred. A dichotomous time-varying covariate was defined,
with the value at time t = 1 if (t >time-EAD), otherwise this covariate was = 0. For treatment with corticosteroids and
COX-2 inhibitors, dichotomous time-dependent variables were defined in a similar way.
When defining the time-dependent variable for DMARDs, the accumulated number of months
of DMARD treatment was also used; at each time t of an event and for every patient in the risk set, we determined the composition of
the risk set and calculated the actual value of the variable DMARD at time t (DMARD(t)). For AUC DAS28, the time-dependent covariate AUC DAS28 was assumed to follow a
step-function in which the values for AUC DAS6, AUC DAS12, and AUC DAS24 remained
throughout the time intervals (0, 12), (12, 24) and (24, 60), respectively.

Cox proportional hazard simple regression models with fixed (time-independent) covariates
were used to identify covariates associated with the first new CVE in the group of
patients that were followed-up for five years following diagnosis (n = 442). For time dependent covariates, Cox extended models were also used with time-varying
variables in simple regression models and in combined regression models with both
fixed and time-dependent variables. Covariates reflecting disease activity, traditional
risk factors for CVD and pharmacological treatment were considered in multiple regression
modelling, based on clinical experience, previous studies and with statistical significance
(P < 0.2) in simple Cox models, and tested in a few appropriate combined models.

All calculations were performed using PASW Statistics 18.0 (SPSS, Chicago, IL, USA).

Results

In all, 700 early RA patients were attending the four rheumatology centres between
December 1995 and April 2008. The first follow-up was in each case made five years
after inclusion (T5); by April 2008, 442 patients had reached the five-year follow-up
(T5). Twenty- three patients had died within the first five years following inclusion.
All patients could be traced at the follow-up.

Table 1. Demographic and clinical data in early RA at baseline (T0) and after five years (T5)

Descriptive data for all patients at baseline (T0) (n = 700) and for those having reached T5 (n = 442) are presented in Table 1. The mean age (standard deviation, SD) of the patient cohort at disease onset was
55.2 (14.3) years; for women this value was 53.7 (14.8) and for men 58.6 (12.6) years.
The mean duration from the first signs of disease symptoms to inclusion at T0 was
6.6 (3.3) months, and was the same in both sexes. Regarding demographic data, the
patient group that had reached T5 (n = 442) did not differ from the whole patient group (n = 700) at baseline. In the patient group that was followed up at T5 (n = 442), all of the variables reflecting disease activity (that is, ESR, CRP, DAS28)
had decreased significantly (P < 0.001 for all three parameters) compared with baseline. The number of tender and
swollen joints, HAQ, VAS pain and VAS global had also decreased significantly (P < 0.001 for all).

At the five-year follow-up (T5), 48 of the 442 patients (27 men, 21 women) (10.9%)
had experienced a new CVE: 15 MI, 4 CABG, 23 stroke/TIA, 5 DVT/LE and 1 ruptured aortic
aneurysm. Twelve of the events were fatal. In all, 23 of the 442 patients died from
various causes during the follow-up period. Fifteen of the 48 patients who had experienced
a new CVE had suffered an event prior to inclusion.

Traditional CV risk factors at T0 and at T5

Data on traditional CV risk factors at baseline and after five years are shown in
Table 2. In patients who had reached T5 (n = 442), treatment for hypertension had increased (P < 0.001) compared with T0, and both systolic and diastolic blood pressure had decreased
significantly (P < 0.01 for both). The proportion of patients with type II diabetes had increased (P < 0.01). Significantly fewer patients were smokers (P < 0.001). BMI had also decreased significantly between T0 and T5 (P < 0.05).

Table 2. Cardiovascular risk factors and treatment in early RA at baseline (T0) and after five
years (T5)

Pharmacological treatment at T0 and at T5

Data on pharmacological treatment are shown in Table 2. A total of 393 patients (88.9%) were prescribed DMARDs within three months following
inclusion (T0) into the study. The mean time between the first symptoms of disease
and DMARD treatment was 7.0 (0.3) months. During the first five years of disease,
the patients had been treated with DMARDs for a mean duration of 51 (16.4) months.
At T5, 429 (96.8%) of the patients were taking, or had been treated with, DMARDs for
some time; 361 (81.5%) had received methotrexate, and 62 (14.2%) had been treated
with biological agents.

Predictors for a new CVE

In the evaluation of predictors of cardiovascular disease, simple Cox models revealed
that an increase in the hazard rate of a new CVE during the follow-up period was predicted
by higher cumulative disease activity (that is, both AUC of DAS28 at six months, and
measured as a time dependent variable) and by progression of extra-articular disease,
in addition to a greater age at disease onset, being male, having had a previous CVE
and to traditional cardiovascular risk factors (diabetes mellitus, treated hypertension,
higher triglyceride level).

Regarding pharmacological treatment, simple Cox models showed that a new CVE during
follow-up was predicted by shorter duration of treatment with DMARDs during follow-up
and treatment with corticosteroids both at/or before inclusion (T0) and during follow-up,
before a new CVE. Also treatment with COX-2 inhibitors before CVE increased the risk
in simple regression analysis. Treatment with DMARDs within three months of disease
onset was protective, analogous to total treatment with DMARDs before a CVE (Table
3).

Table 3. Co-variates for a new cardiovascular event during five years after RA-onset in 442
patients.

The presence of ACPAs, RF, ANA, HLA-SE defined as *0404, *0401 in the present work,
and PTPN22-T polymorphism had no statistically significant impact on the incidence
of CVE.

When the impact of disease activity was evaluated in a multiple Cox model and adjusted
for gender, hypertension and triglyceride level, a higher ESR at baseline independently
increased the hazard rate of a new CVE. Treatment with DMARDs was protective, when
included in the model above (Table 4). Adding age to the model resulted in a P-value = 0.19 for age. There were no significant interactions in the model. Figure
1 illustrates how the hazard ratio of a new CVE is potentiated by the combination of
inflammatory activity (ESR) at baseline and cardiovascular risk factors (based on
the variables in Table 4). The synergistic effect of increasing ESR at baseline and a higher triglyceride
level is more than doubled by the impact of hypertension.

Table 4. Importance of potential risk factors for a new CVE in early- RA followed for five
years.

Figure 1.A new CVE is potentiated by the inflammatory activity and cardiovascular risk factors. Estimated hazard ratio (HR) of a new cardiovascular event, (CVE), at a given time
t during five years follow-up in patients with early rheumatoid arthritis (RA), taking
inflammatory activity (erythrocyte sedimentation rate, ESR) at baseline (T0) and the
level of triglycerides in consideration (median values as reference); A) without and B) with hypertension at baseline. The model also adjusts for gender and disease modifying
antirheumatic (DMARD) treatment.

With a focus on pharmacological treatment, DMARDs given before CVE decreased the incidence
of CVE in the models presented. Treatment with COX-2 inhibitors before a CVE was a
significant predictor of a new CVE in simple analysis. Adjusting for previous CVE
did not change this relationship (HR 2.121, CI 1.072 to 4.2; P = 0.31). The impact of corticosteroid treatment could not predict a new CVE when adjusting
the models for inflammatory activity including a model equivalent to table 4 (data not shown)

Discussion

In patients with newly diagnosed RA followed for five years, a new CVE was predicted
by high disease activity over time, extra-articular disease and by most of the traditional
CV risk factors, that is, the presence of diabetes mellitus and/or hypertension at
inclusion, and the level of triglycerides all predicted significantly a new CVE. Treatment
with DMARDs decreased the risk whilst COX-2 inhibitors appeared to predict a new CVE.

We, and others, have previously shown that inflammatory activity is deleterious for
the progression of CVD [13,15-17] although there are contradicting reports [14]. Most previous publications on CVD in RA are retrospective or cross-sectional and
studies on inception cohorts are scarce. In one previous prospective study from disease
onset, CRP at baseline was found to predict death due to CVD in a cohort comprising
patients with polyarthritis rather than RA [27]. In patients with longstanding RA, CRP could also predict atherosclerosis, as measured
by carotid intima media thickness, over an extended follow-up [28]. In the present study, ESR and CRP at inclusion did not predict future CVE in univariate
analyses. However, when evaluated together with CV risk factors and DMARD treatment,
ESR at baseline had an unfavourable prognostic significance for a new CVE. Furthermore,
cumulative inflammation over time (that is, AUC of DAS28) could predict a new CVE
in simple, as well as independently in multiple, regression analysis. Also, a more
serious disease, as measured by development of extra-articular disease during follow-up,
was associated with a new CVE consistent with previous reports on the predictive effect
of extra-articular disease and RA-vasculitis [26]. Furthermore, an efficient suppression of disease activity, that is, treatment with
DMARDS within three months following the onset of rheumatoid disease, significantly
reduced the hazard of a new CVE as did more intensive DMARD treatment over time; the
latter finding also applied to multiple regression models. It was also apparent that
inflammatory activity is particularly dangerous in patients when combined with the
presence of traditional CV risk factors such as hypertension and hyper-triglyceridaemia.
These results emphasize previous findings by others [17].

Another finding of the present study was that treatment with COX-2 inhibitors was
significantly predictive of a new CVE. Analogous with this, the consumption of COX-2
inhibitors was recently reported significantly more often in patients who developed
an incident CVD in a three-year follow-up [29]. Treatment with COX-2 inhibitors during the first years after this study was initiated
would preferably have been administered to patients with a known increased CVE risk
to reduce the risk of complications such as gastrointestinal bleeding and water retention
with concomitant CV complications. After rofecoxib was withdrawn in 2004, the opposite
situation would be representative; that is, patients with an increased CV risk would
not be treated with COX-2 inhibitors. After adjustment for a previous CVE, COX-2-inhibition
was, however, still significantly predictive of a new CVE in our cohort.

Corticosteroid treatment appeared to be able to predict a new CVE according to univariate
analyses. However, when the inflammatory activity was taken into account, corticosteroid
treatment had no statistically significant impact on the hazard rate of CVE, implicating
confounding by indication as an explanation for the results. Analogous to the findings
presented, most longitudinal studies have not reported low-dose corticosteroid treatment
to be a risk factor for CVD in patients with RA although this is still somewhat controversial
[30]. We, and others, have reported a decreased risk for a new CVE following treatment
with corticosteroids [13,16]. An attractive explanation would be that corticosteroid treatment reduces the deleterious
disease activity by suppressing the inflammatory response. Although corticosteroids
may have pro-atherogenic effects, as shown in patients with SLE [31], the net effect on CVD progression would be positive. A recent histological study
of coronary artery tissue showed more unstable plaques in patients with RA compared
with controls [32]. One possible pathogenic explanation to a favourable effect of treatment with corticosteroids
would be a stabilization of such plaques.

We found that a new CVE was predicted by most of the traditional CV risk factors.
This is at variance with most previous reports in which traditional risk factors have
usually not been found to be of major importance for the development of CVD in patients
with RA [5,10,12,13]. Hypertension increased the hazard ratio, both when measured by ongoing anti-hypertensive
treatment and as raised current systolic and diastolic blood pressure. On this point,
our data confirm previous retrospective studies [3,12,13,16,17,33] that have shown hypertension to be a significant predictor of a first CVE or death
due to CVD. Over time, the treatment of hypertension had increased significantly at
T5. In contrast, blood pressure at inclusion was higher than at the end of the follow-up
period, probably reflecting the greater disease activity at disease onset, or as a
result of anti-hypertensive treatment, and/or a better control of the blood pressure
due to a stringent follow-up.

Diabetes mellitus was also significantly predictive of a new CVE. The influence of
diabetes on future CVD has not been demonstrated in previous studies [5,10,12,13,16] although insulin resistance has been reported in RA patients [34,35]. In the QUEST-RA study, diabetes emerged as an independent risk factor in multivariate
analyses but only for stroke [36].

Regarding hyperlipidaemia, statin treatment at inclusion (which can be considered
a proxy for pre-existing hyperlipidaemia) increased the CV risk whilst a high HDL
level decreased the hazard at statistical levels that were close to significance.
In accordance with most previous studies, the level of total cholesterol was not predictive
of CVD in this RA cohort. Dyslipidaemia, that is, a disturbed ratio of S-LDL/HDL cholesterol,
may be relevant for the development of CVD in RA patients and appears to be dependent
on higher disease activity [37-41]. In the present study, a higher triglyceride level increased the risk of CVE independent
of sex, disease activity, anti-rheumatic treatment and hypertension. This is not consistent
with previous studies [33,38,39,42]. In patients with SLE, hyper-triglyceridaemia is regularly reported as part of the
lipid pattern commonly denoted as "lupus dyslipoproteinaemia" and comprises a decreased
HDL level, an increased triglyceride level and no effect on the cholesterol level
[43]. This pattern is, in SLE patients, associated with disease activity. One mechanism
suggested to be responsible for this pattern is inhibition of lipoproteinlipase activity.
In a previous study on patients with established RA, we found no increase in the level
of triglycerides, but a relationship between lipoproteinlipase and inflammatory activity
[44]. It is possible that the size of the patient cohort and the prospective design of
this study is better equipped to reveal any important role for triglyceridaemia in
atherogenesis in addition to RA. However, the level of LPL was not evaluated in this
study.

The proportion of patients who smoked decreased over time. Smoking is a well-known
risk factor for CVD morbidity and mortality in the general population, but was not
a statistically significant independent predictor for a CVE in this prospective cohort
of patients with RA. Only a few studies have reported an obvious negative impact of
smoking on CVD in RA patients [12]. This is probably not due to smoking being less harmful in these patients but rather
to its relatively small contribution to the total CV risk in patients affected with
chronic inflammation [12].

Additionally, the mean BMI decreased significantly during the first five years of
disease. Although most of the patients were adequately treated, with a mean DAS28
of 3.2 after five years, the decreased BMI may be a reflection of the continuing inflammation
in RA leading to a certain degree of rheumatological cachexia [45]. In previous studies, a low, rather than a high, BMI has been associated with an
increased risk of death due to CVD in patients with RA [46,47]. However, in these patients with early RA, the BMI did not show up as a significant
predictor for a new CVE.

No association between the presence of RF or ACPA and future CVE was found. This is
in contrast to a recent report [48] in which it was claimed that ischaemic heart disease is more frequent in RF- or ACPA-positive
RA patients. However, the patient group in that study was hospital-based implying
a more severe disease state than was present in our community based patient cohort.
Furthermore, their cohort was not inceptional, with a mean disease duration over 10
years. The lack of association between PTPN22 polymorphism and future CVE was on the
other hand in keeping with a recent study [49].

There are several strengths of the present study. First, the patient group comprises
a large regional cohort and the prospective design involves few physicians at each
rheumatology centre. In Sweden, essentially all patients with newly diagnosed RA are
referred to a specialist. Thus, the results for the present cohort can be regarded
to be general and, therefore, applicable to all patients with early RA. Furthermore,
since only patients with very early disease were included, left censorship was avoided.
Furthermore, repeated measurement of the parameters associated with inflammation made
it possible to take variability in disease activity into account. Conversely, a limitation
is the observational nature of this study with a risk of confounding by indication
regarding the effects of pharmacological treatment. We tried to adjust for that by
using multiple regression modelling in the statistical analyses when evaluating potential
predictors of CVE. Another limitation is the relatively small number of events which
restricts the estimation of possible multiple Cox models.

In the present prospective study evaluating risk factors for progression of CVE co-morbidity
in patients with a recent onset of RA, we were able to show that the inflammatory
status, both at disease onset and accumulated over time, was a strong predictor of
a new CVE, with implications also for disease severity, measured as extra-articular
disease. Furthermore, traditional risk factors and disease activity appeared to potentiate
each other. Our data confirm the cardio-protective effect of disease modifying anti-rheumatic
treatment. There were also implications of a harmful effect of Cox-2-inhibitions.
Possibly due to the size and prospective design of this study, it was possible to
show that most traditional risk factors for CVD are also of importance in early RA.
In previous studies, their relative contribution to the total risk may have been concealed
by the strong influence of inflammation. Because traditional CV risk factors are modifiable,
a large effort should be made towards their prevention and treatment, in addition
to the fundamental suppression of disease activity, when monitoring the care of patients
with early RA. Our prospective data may add to the accumulated knowledge in future
development of guidelines for the prevention of CVD in patients with rheumatic disease,
work that is already ongoing in several countries and through international collaboration
[50].

Conclusions

In conclusion, we found that the progression of a new CVE in early RA was predicted
by traditional CV risk factors, that is, the presence of diabetes mellitus and/or
hypertension at inclusion, and the level of triglycerides, and was potentiated by
high disease activity at inclusion and accumulated over time. Our data confirm the
cardio-protective effect of disease modifying anti-rheumatic treatment. Given the
current state of knowledge, it is important to suppress disease activity and great
effort should be made to optimize the prevention and treatment of traditional CV risk
factors in patients with RA.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

LI participated in the design of the study, collected and registered patient data,
contributed to the statistical analysis and drafted the manuscript. AS, LL, BM, SM
and TS participated in the collection and registration of the patient data. MLÖ performed
the statistical analysis and contributed to discussions. SRD participated in the design
of the study, collected patient data and contributed to a great extent to the discussion.
SWJ was the principal investigator, designed the investigation, and participated in
data collection, statistical analysis and drafting of the manuscript. All authors
contributed to discussions and read and approved the final manuscript.

Acknowledgements

The authors thank Dr Antje Braun at the Department of Rheumatology, Sunderby Hospital,
Luleå and nurses Sonja Odeblom and Anne-Cathrin Kallin at the Department of Rheumatology,
University Hospital, Umeå, for excellent help with collection of patient data.

This work was supported by grants from the Swedish Research Council (grant number
K 2003-74XD- 14705-01A), the Swedish Rheumatism Association, the Visare Norr, Norrlandstingens
regionförbund (orthern County Councils) the Medical Faculty of Umeå University, the
Swedish Society of Medicine, the Swedish Heart -Lung Foundation and the Swedish national
project "COMBINE".

Nomenclature and criteria for diagnosis of ischemic heart disease. Report of the Joint
International Society and Federation of Cardiology/World Health Organization task
force on standardization of clinical nomenclature